Miniaturized implantable electrochemical sensor devices

ABSTRACT

An implantable device having a communication system, a sensor, and a monolithic substrate is described. The monolithic substrate has an integrated sensor circuit configured to process input from the sensor into a form conveyable by the communication system.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/457,642 filed on Jun. 28, 2019, which claims priority toU.S. patent application Ser. No. 14/174,827 filed on Feb. 6, 2014, nowU.S. Pat. No. 10,376,146 issued on Aug. 13, 2019, which, in turn, claimspriority to U.S. Provisional application 61/761,504 filed on Feb. 6,2013, the contents of all of which are incorporated herein by referencein their entirety. The present application is related to U.S.application Ser. No. 14/106,701 filed Dec. 13, 2013, herein incorporatedby reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to miniaturized implantableelectrochemical sensor devices.

BACKGROUND

The measurement of biological indicators is of interest for a variety ofmedical disorders. Various systems have been developed to measurebiological indicators from within the living body of various animals(e.g. mammals) via an implantable device.

Existing implantable devices have the potential to create high localtemperatures inside the living body. Often power provided from externalsources results in an increase in local temperature around theimplantable device. Often transmission of information from theimplantable device results in an increase in local temperature aroundthe implantable device

The living body, however, cannot tolerate high internal temperatures.High internal temperatures often lead to tissue death. (Seese,“Characterization of tissue morphology, angiogenesis, and temperature inthe adaptive response of muscle tissue in chronic heating, Lab. Invest.1998; 78 (12): 1553-62).

Another issue facing implantable devices is the formation of a foreignbody capsule in the tissue of the living body around the implantabledevice. Fibrogen and other proteins bind to the device surface shortlyafter implantation in a process known as biofouling. Macrophages bind tothe receptors on these proteins releasing growth factor β and otherinflammatory cytokines. Procollagen is synthesized and becomescrosslinked after secretion into the extracellular space graduallycontributing to formation of a dense fibrous foreign body capsule. Thedense capsule prevents the implantable device from interfacing with theliving body and thereby often hinders the operation of the implantabledevice (Ward, “A Review of the Foreign-body Response toSubcutaneously-implanted Devices: The Role of Macrophages and Cytokinesin Biofouling and Fibrosis”, Journal of Diabetes Science and Technology,Vol. 2, Is. 5, September 2008).

SUMMARY

In one embodiment the present disclosure relates to an implantabledevice comprising a communication system, a sensor, and a monolithicsubstrate comprising an integrated sensor circuit configured to processinput from the sensor into a form conveyable by the communicationsystem, and a an integrated power supply configured to receive energyfrom an external source.

In an alternative embodiment the invention relates a method foroperating an implantable device comprising receiving pulsed power for afirst interval of time at the implantable device and transmitting pulsedinformation for a second interval of time from the implantable device.

Various embodiments of the implantable device of the present enclosurereceive power from an external device and transmit information to anexternal device while maintaining a low local temperature around theimplantable device. Various embodiments of the implantable device of thepresent disclosure result in minimal foreign body capsule formation.

BRIEF DESCRIPTION OF DRAWINGS

The accompanying drawings, which are incorporated into and constitute apart of this specification, illustrate one or more embodiments of thepresent disclosure and, together with the description of exampleembodiments, serve to explain the principles and implementations of thedisclosure.

FIG. 1 illustrates an exemplary embodiment of the circuitry of theimplantable device.

FIG. 2 illustrates an exemplary embodiment of multiple working electrode(WE) switching circuitries and Vsensor current input means.

FIG. 3 illustrates an exemplary embodiment of control circuitry.

FIG. 4 illustrates an exemplary block diagram of the implantable device.

FIG. 5 shows holes formed into a monolithic substrate.

FIG. 6 illustrates an exemplary embodiment of the configuration of theimplantable device.

FIG. 7 shows the formation of pillars on CMOS.

FIG. 8 and FIG. 9 show the coating of pillars.

FIG. 10 illustrates the material coating of the monolithic substrate.

FIG. 11 illustrates various geometries possible for multiple counterelectrode (CE), reference electrode (RE), and working electrodes (WE).

FIG. 12 shows the effect of pulsed energy on tissue temperature usingboth RF and optical energy.

FIG. 13 and FIG. 14 illustrate an exemplary embodiment of theconfiguration of the external device.

FIG. 15 shows an exemplary block diagram of the external device.

FIG. 16 shows an exemplary block diagram of the external device.

FIG. 17 shows the results of data transmission through tissue.

FIG. 18 shows the result of temperature of energy transmission throughtissue.

FIG. 19 shows the sensing of glucose levels over the course of shorttime pulse.

FIG. 20 shows the correlation between current measured by a commercialpotentiostat and that of the implantable device.

DETAILED DESCRIPTION

In an embodiment, the present disclosure relates to an implantabledevice including a communication system, a sensor and a monolithicsubstrate upon which a sensor circuit and a power supply aremonolithically integrated wherein the communication system is located ona first face of the monolithic substrate and the integrated sensor islocated on a second face of the monolithic substrate opposite to thefirst face.

The term “communication system” is intended to have its ordinary meaningin the art. In various embodiments, the communication system cancomprise a single component or a plurality of components in order totransmit information from the sensor circuit to an external device. Forexample in various embodiments according to the present disclosure thecommunication system may comprise an LED, a laser, or an RF antenna. Inembodiments the communication system may transmit a signal incorresponding to the current outputted by the sensor circuit. Inalternative embodiments of the present disclosure the communicationsystem can take more complex forms. For example the communication systemmay comprise a modulator, an output driver, and a transmission system.The communication system may additionally comprise a pulse codemodulator which can be used to modulate the transmitted signal.

A “monolithic substrate” is a substrate, upon which components aremonolithically integrated and therefore such components are not adheredand/or secured via mechanical means to the substrate. In variousembodiments according to the present disclosure the monolithic substratecan be the result of processing using CMOS technology or otherfabrication technology known to the skilled person. It is understoodthat a monolithic substrate has multiple faces, and at least a firstface and a second face. A first and second face can be distinguishedfrom other faces of the monolithic substrate in that the first andsecond face are larger than the other faces of the monolithic substrate.

The term “sensor” refers to the region of the device responsible for thedetection of a particular biological indicator. For example, in someembodiments for glucose monitoring, the sensor interface refers to thatregion wherein a biological sample (e.g., blood or interstitial fluid)or portions thereof contacts an enzyme (e.g. glucose oxidase); areaction of the biological sample (or portion thereof) results in theformation of reaction products that allow a determination of the glucoselevel in the biological sample. In various embodiments of the presentinvention, the sensor further comprises a “functionalization layer” asdescribed later in the present disclosure. In various embodiments ofpresent disclosure the sensor can be monolithically integrated into themonolithic substrate. In various embodiments of the present disclosurethe monolithically integrated sensor can be placed on a different faceof the monolithic substrate from the power supply. This can be done invarious embodiments by forming for example high surface electrodessimilarly to the method described below on a silicon face of themonolithic substrate and interconnecting them through the monolithicsubstrate to the other face of the monolithic substrate comprising thepower supply.

The term “power supply” is intended to have its ordinary meaning in theart. In various embodiments according to the present disclosure thepower supply can comprise an RF antenna or photovoltaic cell forreceiving external energy.

Various embodiments according to the present disclosure may be ofdifferent sizes. In various embodiments the device will be less than 1mm long and 1 mm wide with a height of less than 200 microns. In variousother embodiments the device will have a height of less than or equal to200 or 100 microns and a length and a width of less than or equal to 500microns.

In various embodiments the device according to the present disclosuremay comprise a sensor circuit. The sensor circuit can comprise a circuitthat processes signal from the sensor into a form easily conveyed by thecommunication system. In various embodiments the sensor circuit mayconsist of a potentiostat. In alternative embodiments the sensor circuit102 may comprise a potentiostat 107 and a current mirror 108 as seen inFIG. 1 .

A modulator as understood in the present disclosure indicates a circuitthat varies one or more properties of a periodic waveform in response tovariations in an input of the modulator provided by the sensor circuit(e.g. modulation signal). In various embodiments according to thepresent disclosure the modulator can comprise a pulse-width modulator104 that increases the width of a pulse sent from the device (e.g. tothe input of the modulator) depending on an output (e.g. current output)of the sensor circuit 102.

Various embodiments of the present disclosure comprise an output driver.In some embodiments according to the present disclosure an output drivercan increase a current provided by the modulator output such as to allowtransmission at an acceptable power level of the modulator output by thetransmission system of the implantable device. In various embodimentsthe output driver 105 may comprise one or more transistors possiblyhandling a large current that increases the current provided by thepulse width modulator 104.

A transmission system in the as described through the present disclosuremay comprise a laser (e.g. VCSEL), LED, RF antenna.

The term “potentiostat,” is used herein, in its ordinary sense,including, without limitation, an electrical system that controls thepotential between the working and reference electrodes of at least athree electrode cell at a present value. It controls a current thatflows between the working and counter electrodes to keep the desiredpotential, as long as the needed cell voltage and current do not exceedthe operational limits of the potentiostat.

An example of a potentiostat circuit 107 is seen in FIG. 1 . Thepotentiostat 107 includes electrical connections to a working electrode(WE), reference electrode (RE), and a counter electrode (CE). In variousembodiments according to the present disclosure multiple workingelectrodes (WE) could be used via transistor switching as seen in FIG. 2. In FIG. 2 transistor switching is used to switch between n workingelectrodes (e.g. WE1, WE2, WEn) via opening or closing switches W1, W2,Wn by an isolated voltage provided to each switch (W1, W2, Wn). Invarious embodiments the switching voltage to open transistor switchesW1, W2, and Wn may come from an external source (e.g. photovoltaic). Thevoltage applied to the working electrode WE and the voltage applied tothe reference electrode RE are set such that the voltage differenceapplied between the working electrode WE and reference electrodes RE ismaintained at a constant value or swept between values (e.g. voltages).The counter electrode CE is configured to have a current equal to theamount measured by the working electrode WE by varying the voltage atthe counter electrode CE to balance the current going through theworking electrode WE such that the current does not pass through thereference electrode RE. This can be accomplished by an OP AMP 110 with anegative feedback loop connected to both the reference electrode RE andcounter electrode CE. The input current for the OP AMP 110 Vsensor canin various embodiments according to the present disclosure from begenerated from the power supply itself 202 or an independent photodiode203 as seen in FIG. 2 .

A current mirror is a circuit well known by a person skilled in the artand which is used to control a current output independent to a loadingpresented to the circuit. An example of a current mirror can be seen inFIG. 1 at 108. The current mirror in this exemplary embodimentreplicates the sensor current from the potentiostat 107 without actuallyloading the potentiostat 107 thereby isolating its performance. In thisexemplary embodiment depicted in FIG. 1 of the present disclosure thecurrent from the potentiostat 107 (“Isensor”) is mirrored by the currentmirror 108 via matching transistors.

A control circuit can control energizing of the various components ofthe implantable device. In various embodiments of the present disclosurea control circuit 103 can be present such as to control operation of thedevice while in alternative embodiments the current from the sensormirror 108 can flow directly into the pulse width modulator 104. In oneembodiment of the present disclosure the control circuit 103 receives acurrent from the current mirror 108 and the control line (control). Acurrent into the transistor of the control circuit 103 from the controlline enables the current from the current mirror 108 to enter the pulsewidth modulator 104, input driver 105, and transmission system 106. Thecontrol circuit 103 serves as a switch which when enabled via thecontrol line “control”, enables operation of the modulator and therebytransmission of data by the device. The control line can be connected toan oscillator as seen at 301 of FIG. 3 or a photovoltaic cell as seen at302 of FIG. 3 . The timing of the oscillator 301 can be controlled bythe relative ratios of the transistor sets (e.g. x and y). Theoscillator 301 can result in voltage to the control line (control) atshort regular intervals relative to intervals as seen in the graph ofFIG. 3 . In various embodiments, the photovoltaic cell at 302 can beactivated by a different wavelength than that of the power supply orother photovoltaic cells on the implantable device thereby providingcontrol over the activation of the pulse-width modulator 104 and theinput driver 105 and transmitter system 106. By limiting an ON time ofthe pulse-width modulator 104, input driver 105, and transmitter system106 the implantable device can limit the amount of heat generated by thedevice. The temperature is limited by limiting the power transmitted bythe transmitter system 106 under control of the control circuit (whenpresent). The temperature is limited because minimal heat is generatedby the pulse width 104 modulator and output driver 105 because saidsystems are at some time periods not activated.

A pulse width modulator can comprise various circuits to transform thecurrent from the current mirror 108 and control circuit 103 into aseries of pulses. According to one embodiment of the present disclosure,depending of the current from the current mirror 108 and the controlcircuit 103, the pulse width modulator 104 varies the width of thepulses generated via an internal oscillator 109. The pulse widthmodulator 104 then feeds the pulses into the input driver 105 andtransmission system 106. It should be noted that under control of the“control” signal, the control circuit, during an active portion of thedevice, provides current from the sensor circuit (e.g. current mirror)to the lower section of the modulator (104) and therefore enablesoperation of the modulator as enabling the lower section can allow acurrent flow from the top section to the lower section of the modulator(104).

The function and interrelationship of the communication system 9, sensor7, power supply 3, and sensor circuit 4 is illustrated in an exemplaryembodiment of the present disclosure of FIG. 4 of the presentdisclosure. In this embodiment, the power supply 3 is operably connectedto the communication system 9, sensor circuit 4 and sensor 7. Thecommunication system 9 receives a processed signal from the sensorcircuit 4 which is operably connected to the sensor 7.

In an exemplary embodiment according to the present disclosure thecommunication system 9 comprises a modulator 5, output driver 6, andtransmission system 8. In such an embodiment the power supply 3 isoperably connected to the modulator 5, output driver 6, transmissionsystem 8, sensor circuit 4, and sensor 7. The sensor circuit 7 isoperably connected to the modulator 5 that modulates the informationfrom the sensor circuit 4. The information is sent to the output driver6 where a corresponding power of the modulated information is increasedand subsequently fed to the transmission system 8 of the implanteddevice for transmission.

A working electrode is an electrode in an electrochemical system onwhich a reaction of interest is occurring. The working electrode isoften used in conjunction with a counter-electrode, and a referenceelectrode in a three electrode system. Common working electrodes canconsist of noble metals such as gold, silver, and platinum. Exemplaryworking electrode in the subject invention further includes high surfacearea electrodes.

A reference electrode is an electrode which has a stable and well-knownelectrode potential. Example reference electrodes include electrodesmade with inert metals such as gold, silver, platinum and silver/silverchloride.

A counter electrode is an electrode commonly used in a three-electrodesystem for voltammetric analysis. In a three-electrode cell, the counterelectrode can be used to provide a circuit over which current is eitherapplied or measured. The potential of the counter electrode is usuallynot measured and can be adjusted so as to balance the reaction at theworking electrode. A counter electrode in various embodiments can befabricated from a variety of chemically inert materials such as gold,platinum, or carbon.

In various embodiments the implantable device can comprise 1, 2, 3, 4 ormore working electrodes as previously discussed in the presentdisclosure in connection to FIG. 2 . In glucose sensing, embodimentsglucose oxidase is used to produce hydrogen peroxide from glucose andthereby the oxygen to drive the sensor; however, glucose oxidase candegrade from a variety of mechanisms when implanted within the body suchas thermal and chemical denaturing as well as protease degradation. Itfollows that according to further embodiments of the present disclosure,a novel protected working electrode is presented which can increase thetotal longevity of implantable devices according to the presentdisclosure can be increased.

In various embodiments at least one electrode can be coated with abiodegradable polymer as to protect the electrodes for a time frame.Biodegradable polymers are non-toxic, capable of good mechanicalintegrity until degraded, as well as capable of a controlled rate ofdegradation. Examples of suitable biodegradable polymers includepolyglycolide (PGA), polylactide (PLA), and polycaprolactone (PCL). Saidpolymers can be applied to the device by pipetting onto the portion ofthe device displaying the electrode.

A photovoltaic power supply is a power supply that creates electricalcurrent upon exposure to light which can be related to the photoelectriceffect. When light is incident upon a material surface, the electronspresent in the valence band absorb energy and, being excited, jump tothe conduction band and become free. These highly excited, non-thermalelectrons diffuse, and some reach a junction where they are acceleratedinto a different material by a built-in potential. This generates anelectromotive force, and thus some of the light energy is converted intoelectric energy. An example of a photovoltaic power supply implementableon a monolithic substrate would include for example a p-n junction solarcell.

A CMOS die is a die that is designed for CMOS processing. Examples ofcommercially available CMOS include dies from TSMC 250 nm and IBM 250nm. The skilled person will know of other technologies and processeswhich can be used for monolithic integration.

Various embodiments comprise a hole that passes from a first side of themonolithic substrate to a second side of the monolithic substrate. Holescan be made using a variety of different methods. UV laser ablation canbe used to make holes as corresponding wavelengths can ablate bothdielectrics and silicon layer. Gas based etching can also be used.Pseudo-Bosch process is an example of plasma processing. Holes resultingfrom a pseudo-bosch process can be seen in FIG. 5 of 30 micron size.

In various embodiments a hole 607 or holes can be used to allowimplantable device to be secured to bone or various other tissues via ametal, fiber or polymer based insert that fits into the hole. In variousembodiments the hole or holes can be located in different regions of thesubstrate. In various embodiments 1, 2, 3, 4, or more holes can beprovided.

In various embodiments, holes can allow liquid to pass through thedevice. Holes by allowing liquid to pass through the device may minimizeforeign body capsule and in various instances may prevent clogging ofthe circulatory system by allowing passage of circulatory fluid even ifthe device becomes lodged in a circulatory vessel.

An interconnect may links two regions of the implantable device, suchas, for maybe, different faces of the implantable device. Hereininterconnects 608 of FIG. 6 can be conductive material such as copperthat can connect to different components or provide connections withincomponents on the monolithic substrate 601.

An exemplary interrelationship of a communication system and sensorcircuit 606, sensor 602, power supply 609 can be seen in FIG. 6 . InFIG. 6 the communication system 606 is on first face the monolithicsubstrate 601 and the sensor 602 is located on a second face of themonolithic substrate 601. In FIG. 6 the sensor comprises 3 electrodes: asingle counter-electrode 603, a single reference electrode 604 and asingle working electrode 605. In FIG. 6 the monolithic substrate 601comprises a hole 607. The sensor 602 is connected to the communicationsystem and sensor circuit 606 via interconnects that electronically linka first face of the monolithic substrate with a second face of themonolithic substrate.

High surface area electrodes can mean an electrode with a surface areaexceeding the classic dimensions of its surface. Further disclosurerelated to high surface area electrodes can be found in U.S. applicationSer. No. 14/106,701, filed on Dec. 13, 2013, herein incorporated byreference in its entirety. In various embodiments according to thepresent disclosure the high surface area can be formed by pillars.

In exemplary embodiments according to the present disclosure the designof the pillars can be made using commercial software. PMMA 950 A4 can beused to achieve clean lift-off while still achieving a desiredresolution. The resist can be spun at 4000 rpm for 1 minute followed bya 180° C. bake for 5 minutes. A dose of 1200 μc/cm² can be used to writethe pattern in a Leica EBPG5000+ optical system. Patterns can bedeveloped in 1:3 solution of MIBK and IPA for 20 seconds followed by adeionized water rinse. Afterwards, a 50 nm alumina mask can be sputtercoated in a Temescal TES BJD-1800 DC reactive sputter system bydepositing aluminum in oxygen plasma for 5 minutes. Lastly, mask liftoffcan be performed in dicholoromethane in an ultrasonic bath for 2minutes. Successful patterning was confirmed by optical microscopy (notshown).

In exemplary embodiments according to the present disclosure patterningcan next be performed with a MA-N 2403 resist. Pillars were fabricatedusing both dry plasma (Cl₂:BCl₃) as well as wet etchants (e.g. TMAH) toetch away parts of the metal pad using a UNAXIS RIE machine. For the dryplasma (Cl₂:BCl₃) etch, the temperature was set to 25 degrees Celsiusand RIE power to 120 watts. Flow rate for Cl₂ was set to 4 SCCM and theflow rate of BCl₃ was set to 20 SCCM. For the wet TMAH etch the surfacecan be submerged in a liquid for room temperature for 10 minutes. Aresulting exemplary embodiment according to the present disclosure usingthe above procedure can be seen in FIG. 7 . Success can be seen in thedimensions and uniformity of the formed structure.

In exemplary embodiments according to the present disclosure, metaldeposition sputtering can be used to perform conformal coatings. Firsthigh density Argon plasma of 20 mTorr is used to increase the isotropyof the deposition. A 5 nm Ti adhesion layer is DC sputtered and then 50nm or 100 nm Au or Pt films were DC sputtered. Resulting embodimentsaccording to the present disclosure using the above procedure can beseen in FIGS. 8-9. A special stage was used which could tilt the samplewith respect to the incoming metal atoms at angles up to 90° C.Secondly, the stage could rotate at speeds up to 120 r.p.m. Acombination of tilt and rotation along with optimization of plasmaparameters (high pressure, around 20 mTorr) resulted in very uniformlycontrolled conformal sidewalls.

A material substantially covering all the device except for theelectrode and laser can be accomplished by a variety of techniques inthe art and in a variety of geometries. In various embodiments SU8,Parylene, PDMS, or Silicone are used. Parylene is applied using vacuumdeposition.

FIG. 10 shows embodiments of the implantable device with a material 1002for protecting the “functional layer” (1001 and 1005) of the electrodes.In this exemplary embodiment the material 1002 surrounds both a firstfunctional working electrode (beneath 1005) and a second functionworking electrode (beneath 1001). Wells have also been formed by thematerial 1002 for the counter-electrode 1004 and the reference electrode1003. The well can be shaped differently to correspond to differentelectrode configurations. In various embodiments the material covers theimplantable device except for the electrodes thereby supporting thefunctionalization matrix (not shown). In various embodiments thematerial substantially covers the implantable device except for theelectrodes and transmission system (not shown).

In one exemplary embodiment according to the present disclosure tosubstantially cover a material comprising a compatible polymer, SU8 canbe applied to the entire surface of the device by spinning at 2000 rpmfor 1 minute followed by a bake at 95° C. for 5 minutes. Next a dose ofU.V. light at 365 nm can be used to write a pattern corresponding to theelectrodes in a Carl Suss mask aligner system for 6 seconds. Afterexpose the device can again be baked at 95° C. for 5 minutes. Patternscan be developed in SU8 developer solution for 5 minutes followed by awater rinse.

In various embodiments the electrodes are covered by a “functionallayer” to provide specificity to a target of interest. The phrase“functional layer” refers to a layer comprising any mechanism (e.g.,enzymatic or non-enzymatic) by which a target of interest can bedetected into an electronic signal for the device. For example, someembodiments of the present invention utilize a functional layercontaining a gel of glucose oxidase that catalyzes the conversion ofglucose to gluconate: Glucose+O₂->Gluconate+H₂O₂. Because for eachglucose molecule converted to gluconate, there is a proportional changein the co-reactant O₂ and the product H₂O₂, one can monitor the currentchange in either the co-reactant or the product to determine glucoseconcentration. In various embodiments of the present disclosure thefunctional layer can comprise a hydrogel (e.g. BSA) loaded with anenzyme (e.g. glucose oxidase). In various alternative embodiments of thepresent disclosure the functional layer can also be a polymer (e.g.polypyridine) loaded with an enzyme (e.g. glucose oxidase).

In various embodiments according to the present disclosure the counterelectrode can be an order of magnitude larger or more than the workingelectrode. The counter electrode can be larger in order to not limit theworking electrode in any way and hence not limit the cell impedance. Invarious embodiments the potential across the working and counterelectrode is pulsed. The working electrode and the counter electrode ofimplantable device require oxygen in some embodiments when detectingglucose. Within the functionalization layer above the electrode oxygenis required for the production of hydrogen peroxide from glucose. Thehydrogen peroxide produced from the glucose oxidase reaction furtherreacts at the surface of the working electrode and produces twoelectrons. The products of this reaction are two protons (2H⁺), twoelectrons (2e⁻), and one oxygen molecule (O₂). The oxygen concentrationnear the working electrode, which is consumed during the glucose oxidasereaction, is replenished by the second reaction at the workingelectrode; therefore, the net consumption of oxygen is zero. The counterelectrode uses oxygen as an electron acceptor. The most likely reduciblespecies for this system are oxygen or enzyme generated peroxidase. Thereare two main pathways by which oxygen may be consumed at the counterelectrode. These are a four-electron pathway to produce hydroxide and atwo electron pathway to produce hydrogen peroxide. Oxygen is furtherconsumed above the counter electrode by the glucose oxidase.

In various embodiments the working electrodes of the device can be laidwith varying degrees of symmetry. FIG. 11 shows embodiments withmultiple working electrodes (WE). In configuration 905 three workingelectrodes (903) are arranged equally distant from the counter electrode901 and reference electrode 902. In configuration 904 eight workingelectrodes (903) are arranged inside an octagonal counter electrode 901with each working electrode (903) equally distant from an equivalentsurface distance of the reference electrode 902 and the counterelectrode 801. Configurations such as 904 where each working electrode903 appears spatially similar to alternative working electrodes 903 mayminimize the need of recalibration. Recalibration may be needed indifferent geometries if the spacing difference of the electrodes mayaffect performance of the reaction. Additionally, the use of such asymmetric configuration as depicted in FIG. 11 may allow use of sameelectronics as the implantable device switches from one workingelectrode to a different working electrode. Such switching may depend onvarious needs such as glucose oxidase degradation and exposure ofalternative electrodes by biodegradable coating degradation.

An embodiment of the present disclosure comprises a method for operatingan implantable device comprising receiving power for first interval oftime at the implantable device and transmitting information for a secondinterval of time from the implantable device.

Power received by the implantable device in various embodiments cancomprise forms such as electromagnetic (light), mechanical, thermal,vibrational (sound waves), or electrical. In an exemplary embodiment thepower is optical (e.g. near infrared, 700 to 1000 nm).

An interval of time for receiving power (e.g. by the implantable device)in various embodiments can span from microseconds to tens of seconds,greater than about 0.1 seconds but less than about 5 seconds, or greaterthan about 0.5 seconds but less than about 2 seconds. In embodiments ofthe implantable device wherein the implantable device comprises at leasta modulator, the interval of time for receiving power can exceed amillisecond.

Transmitting information (e.g. information corresponding to the sensedsignal of the implantable device, information corresponding to the levelof glucose) for an interval of time can comprise transmittinginformation for a period spanning from microseconds to tens of seconds,an interval of time of greater than about 0.1 seconds but less thanabout 5 seconds, or an interval of time greater than about 0.5 secondsbut less than about 2 seconds.

In various embodiments according to the present disclosure the firstinterval of time can substantially equal the second interval of time.Such a configuration can be seen when the potentiostat 107 is directlyconnected to the output driver 105 and hence the transmission system106. In various embodiments according to the present disclosure thesecond interval of time can be contained within the first interval oftime.

Any electronic device has a minimum amount of power needed to drive thecircuitry of the device and continuously providing said power to animplantable device can result in a high temperature in the local regionsurrounding the implantable device. A high temperature in tissue of aliving body can result in damage to the tissue. A potential solutionaccording to the present disclosure devised to avoid a high temperaturecan be to receive power only for certain intervals and transmittinginformation for only certain intervals or in alternative embodiments ofthe present disclosure sub intervals of the intervals. Time versus powerwith RF and optical power pulses was calculated. The results are seen inFIG. 12 . In FIG. 12 it can be seen that during a pulse of energy (1202,1204) a device can receive an amount of power without reaching thesteady state temperature associated with continuous powering of device(see 1201 and 1203). The difference between the steady state temperatureassociated with a given amount of energy and that found when the poweris pulsed can be seen at 1205. Hence various embodiments of the presentdisclosure can relate to powering and transmitting information in shortpulses thereby maximizing the difference in temperature between thesteady state and pulsed operation while permitting powering of theimplantable device and while delivering enough information to understandthe status of the reaction monitored by the sensor (i.e. theconcentration of glucose).

The use of such short pulses may go against common practice as oftendevices require an extended period of time to completely stabilize (e.g.the wavelength of some lasers may vary before reaching steady stateafter continuous powering). This variance associated in operatingtemperature of the device from a steady state temperature with shorterpowering can be undesirable in medical applications where performance iscritical before realizing the temperature advantages of the presentdisclosure.

Powering the device for only an interval of time corresponding to aperiod of time the power is received means that the device at times whenno power is received is powered down and thereby at a steady statecorresponding to a received background power (e.g. from backgroundlight).

In various embodiments, a fraction of a second can be sufficient for anoptical readout according the present invention to capture data to anexternal device. Such embodiments can, for example, be obtained when thesystem is designed for pulse communication schemes. For example, forelectrochemical waveforms for biological sensing, the fastest scan rates(e.g. for cyclic Voltamograms or Chronoamperometric measurements) arefew Hz at most. Hence, a system designed to operate at KHz can easilycapture (send/receive) this data in real-time. The same can be true forRF and acoustic methods used to detect such slowly changing signal.

In various embodiments, the pulse intervals can be used in activelytransmitting systems or a passive communication scheme where a focusedinput beam is modulated by the communication system.

In various embodiments, the receiving a signal separate from thereceiving power to initiate the transmitting of information for aninterval of time can allow the power source to power the device and thencan allow a separate signal from an external device to controlinformation flow when desired from the internal device (e.g. allows theexternal device to set a time period after powering the device until thetransmittal of the blood glucose level).

In various embodiments, the power received is at a different wavelengththan the wavelength of the power transmitted. This reduces interferenceof the transmitted signal and allows wavelength-based filtering at anexternal device.

An embodiment of the present disclosure comprises a system comprising animplantable device as described above and an external device including aprocessor connected to a power transmitter and a power source, theprocessor configured to activate the power transmitter only for certainintervals.

In various embodiments the external device can comprise a power source1501, processor 1502, detector 1503, transmitter 1506, display 1504, andcommunication link 1505. In various embodiments these components canfurther comprise various components (e.g. power source 1501 comprising asolar cell 1510, a power management chip 1511, and a battery 1512). Invarious embodiments the external device can comprise additionalcomponents such as a push switch 1507, buzzer 1508, and/or touch sensor1509.

A processor 1502 is a component that carriers out instructions of acomputer program by performing the basic arithmetic, logical, andinput/output operations of the system. In various embodiments, theprocessor can be a microprocessor that incorporates all the functions ona single integrated circuit. The exact processor of the system can vary.In various embodiments of the present disclosure the processor chip 1502can be a K20P64M72SF1 from Freescale Semiconductor and is operablyconnected to an display 1504, pulse switch 1507, buzzer 1508,communication link 1505, power transmitter 1506, touch sensor 1509,detector 1503, and power management chip 1511 as seen in FIG. 16 . Insuch an embodiment the processor 1502 receives power from the powermanagement chip 1511 and executes a timing program thereby pulsing powertransmitter 1506. The processor also delivers power via its connectionto the display 1504, pulse switch 1507, buzzer 1508, communication link1505, power transmitter 1506, touch sensor 1509, and detector 1503. Theprocessor 1502 processes the information from the detector 1503 anddisplays said information on the display 1504. The processor powers upthe device via the pulse switch 1507. The processor 1502 transmitsinformation concerning the detector 1503 via the communication link1505.

The processor runs an application in all embodiments of the presentdisclosure in which energy is only transmitted by the power transmitterat certain intervals of time. In various embodiments the interval oftime for transmitting power can span from microseconds to tens ofseconds, greater than about 0.1 seconds but less than about 5 seconds,or greater than about 0.5 seconds but less than about 2 seconds.

The power source 1501 can in various embodiments comprise a variety ofcomponents. For example power could be provided by movement of theexternal device being translated into electrical current as seen in somemodern watches. In alternative embodiments the power source can comprisea battery or photovoltaic cell. In various embodiments the power sourcecan comprise a combination of components such as a power management chip1511 (e.g. MC34704AEPR2 from Freescale Semiconductor), solar cell 1510(e.g. AM-1801CA from Sanyo Energy), and batter 1512 (e.g. ML-6215/ZTN).In such one embodiment of such a configuration the power management chip1511 is operably connected to

The power transmitter 1506 can in various embodiments comprise a varietyof components. In various embodiments the power transmitter can be alaser or LED. In various embodiments the power transmitter can includean LED w/driver 1506 opertable connected to the processor chip 1502 asseen in FIG. 16 (e.g. NT-41A0-0482 from Lighting Science GroupCorporation).

In various embodiments of the present disclosure, the external devicecan include a pulse switch 1507 operably connected to the processor 1502such as TL3315NF250Q from E-switch or others as would be known to thoseskilled in the art. In various embodiments of the present disclosure theexternal device can include a touch sensor 1509 operably connected tothe processor 1502 such as TSSELECTRODEE VM-ND from FreescaleSemiconductor or others as would be known to those skilled in the art.In various embodiments of the present disclosure the external device cancomprise a buzzer 1508 operably connected to the processor 1502 such asTE-HCS0503A-H2.5 from Tianer Technology. The buzzer 1508 via a signalfrom the processor 1502 can alert can attempt to wake a user with a lowglucose level. When the buzzer 1508 does not wake the used the processoras detected by an interface of the external device by the use, theexternal device can in various embodiments of the present disclosuresend a signal via the communications link 1505 directly or indirectly(via iPhone) to authorities (e.g. 911) to provide aid to the user.

In various embodiments the detector 1503 can be a CCD or an array ofCCDs. In various embodiments the 1503 detector can be an array such asTC341-30-ND from Texas Instruments that is operably connected to theprocessor chip 1502 as seen in FIG. 16 .

The detector will have to detect the signal transmitted by the implanteddevice. Since the signal transmitted by the implanted device can beweaker compared to background noise (e.g. wavelength), the detector hasto be able to filter out other wavelengths especially the powertransmitter wavelength and the background light. Filtering of thebackground can be done by measuring the light from a period when theimplantable device is not transmitting and subtracting said light fromthe signal. Filtering of the background can also be accomplished invarious embodiments of the present disclosure by means of a physicalfilter.

In some embodiments the detector will be an array (e.g. of detectors).The array allows the detector to detect a signal from the communicationsystem of the implanted device when the implanted device and theexternal device are misaligned with respect to the detector. The size ofone element of the array can be such as to receive maximum power fromthe communication signal to optimize the signal to noise ratio. Sucharray may be designed differently for different applications based onthe tissue scattering response in different areas of the body. Also thedetector in certain embodiments would have low-noise high-gain front endto detect a potentially weak signal.

The display 1504 of the external device of the system can in variousembodiments comprise a watch face, LCD, OLED, or any other means forpresenting information from the processor as can be understood by a user(e.g. a color display, mechanical watch hand). In various embodimentsthe display 1504 can be an LCD display such as C-51847NFJ-SLW-AEN fromKyocera Industrial Ceramics Corporation that is operably connected tothe processor chip 1502 as seen in FIG. 16 .

The communication link 1505 according to the present invention cancomprise a communications means such as but not limited to Bluetooth,USB, and Wi-Fi. In various embodiments the communication link 1505 canbe a Bluetooth module such as LMX9830 from Texas instruments that isoperably connected to the processor chip 1502 as seen in FIG. 16 .

A consumer electronic device is electronic equipment intended foreveryday use. Examples include MP3 players, videorecorders, digitalcameras, and mobile telephones. In various embodiments the consumerelectronic device will be a mobile telephone with a flash as well as acamera element. The dimensions of such a mobile telephone are to beunderstood to be less than about 1 foot long and less than about 6inches wide and 4 inches tall.

An exemplary embodiment of the present disclosure of the various specialconfigurations of the power transmitter 1403, detector 1402, display1302, power source 1303, processor 1304 and communication link 1305 canbe seen in FIGS. 13 and 14 . The display 1302 is on the top side 1301 ofthe external device and is positioned to the side of a processor 1304,power sources 1303, and communication link 1305. The detector 1402 andthe power transmitter 1403 are on the bottom side of the externaldevice. The power transmitter 1403 is positioned distant from thedetector 1402 to potentially avoid interference thereof.

EXAMPLES Optical Testing

The inventors tested optical power and optical communication through a 5mm chicken skin and tissue. The device was placed behind the skin andtissue sample as seen in FIG. 15 . The device was connected to afunctional generator. In front of the skin and tissue sample waspositioned a power laser (0.8 w, 800 nm) and a detector (compoundsemiconductor). In front of the power laser was placed a mechanicalshutter. The mechanical shutter was programed to open for time period of3 milliseconds with an off time of 1 millisecond. The device receivedpower from the power laser through the tissue sample. Using the powerreceived the device transmitted a sine wave 1601 across the chicken skinand tissue and said signal was received 1602 by the detector as seen inFIG. 17 .

The effect of pulsing and optical power was further evaluated.Specifically, the temperature effect of laser transmission thru tissuewas modeled. An implantable device was simulated to be at a 3.5 mm depthinside tissue. In FIG. 18 the vertical and horizontal axis representsdistance in microns with the 0 being where the implantable device waslocated. The side scale of FIG. 18 represents temperature in Celsiuscorrelated to shading. It was found for the specific case of 1 W laserirradiation in the near IR wavelength of 805 nm on the spot of 1 mmsquare time periods around a second are safe. The 1 W laser was placedabove the tissue as in greater than 3500 microns from the implantabledevice. Times on the orders of 10's of seconds for similar amount ofpower delivery were found to create temperatures that could potentiallycause issue damage.

Glucose Testing

Glucose testing was performed with phosphate buffer saline solution in abeaker. The sensor was dipped in the solutions carefully so that onlythe sensor part is exposed to the solution. Insulating epoxy (5 minuteepoxy) was used as the material to substantially cover the implantabledevice. A small vice was used to deploy the epoxy everywhere except thesensor. Solutions with different glucose concentrations, in thephysiological range of 0 mM-20 mM, were made. The device was dipped inthese solutions and the resulting current from the sensor was measured.The experiment was repeated multiple times for multiple sensors. Thesensor was also connected to external electronics (externalPotentiostat) to confirm its working. The performance of the device intesting glucose in small time intervals was confirmed in FIG. 19 atthree different concentrations 0 mM (1801), 1 mM (1802), 2 mM (1803),and 10 mM (1804). A comparison between the device performance and theperformance of an external reference potentiostat CHI 1242B is seen inFIG. 20 .

Biological Testing—A measurement of Foreign Body Capsule UponImplantation of Foreign Device

Formation of a foreign body capsule is a response of the immune systemto foreign materials in a living body. The usual outcome of a foreignbody capsule is the formation of capsules of tightly-woven collagenfibers, created by the immune response to the presence of foreignobjects surgically installed into a living body.

In order to test for the presence or absence of foreign body capsuleupon implantation of the device, 3 mice were tested with subcutaneousinsertion of the device of the present application which is 500 micronsby 500 microns by 200 microns. A second set of 30 mice can then betested with subcutaneous insertion of a device which was 4000 microns by4000 microns by 200 microns. Postoperatively, animals can be imagedusing live scan micro CT (SkyScan 1176 by Microphotonics) to evaluatethe initial shape and orientation of the implants which can be placed atthe abdominal region of the mice. Safety assessment can be based onevaluating the biological response to the device and using the live scanmicro CT, which can be used to determine that the orientations of thedevice, the presence of scar tissue formation or foreign body capsulesurrounding the implantation device at 0, 3, 6, 0 12, 15 and 18 days.

At 30 days, the mice can then undergo another live scan to examine thepresence of foreign body capsule and then the mice can undergoexplantation to examine the tissue that surrounds the device.

Potential local effects of the implant can then assessed for abnormaltissue reactions at the time of explantation by macroscopic evaluationof the foreign body capsule tissue surrounding the implant and byhistological and cellular morphological analysis of this tissue.

Biological Testing—Capsular Contracture Tissue Histology

Potential local effects of the implanted device can be assessed forabnormal tissue reactions at the time of explantation by macroscopicevaluation of the foreign body capsule tissue surrounding the implantand by histological and cellular morphological analysis of this tissue.The histology of the excised tissue capsules can indicate if thecapsules formed show a normal wound-healing response, by examination ofthe presence of inflammatory cells and can be scored from this (scoresof 0 and 1 on a scale of 0 to 5, with 0 being no visible cells in fieldof view at 400×). Inflammatory cells can include neutrophils,lymphocytes, and macrophages and can then be identified by histologicaland cellular morphological analysis. Microscopic examination can then beused to show edema, congestion, necrosis, hemorrhage, or granulation ofthe tissue cells. This can be followed by tissue histology to look forsigns of degeneration, bacterial infection, or malignancy in any of thecapsules, if the capsules are present.

Biological Testing—Tissue Capsule Thickness

The tissue capsule thickness over the device can be examined for the twogroups of mice and can be consistent with the capsule thickness over theentire device. It can be expected that the capsule thickness over theimplantable device will range across the mice from the two groups, themice with the device that is 500 microns by 500 microns by 200 micronsand the mice that are implanted with a device that is 4000 microns by4000 microns by 200 microns. The relative size of the neovascularizationbed was scored by assessing the width of the area from theimplant/tissue interface to the unaffected areas that had thecharacteristics of normal tissue and normal vascularity. This is doneafter 30 days of implantation on the tissue surrounding the explanteddevice.

The mice with the small 500 microns by 500 microns by 200 microns thanthe 4000 microns by 4000 microns by 200 microns will be found to haveless foreign body capsule formation.

A number of embodiments of the disclosure have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the presentdisclosure. Accordingly, other embodiments are within the scope of thefollowing claims.

The examples set forth above are provided to those of ordinary skill inthe art as a complete disclosure and description of how to make and usethe embodiments of the disclosure, and are not intended to limit thescope of what the inventor/inventors regard as their disclosure.

Modifications of the above-described modes for carrying out the methodsand systems herein disclosed that are obvious to persons of skill in theart are intended to be within the scope of the following claims. Allpatents and publications mentioned in the specification are indicativeof the levels of skill of those skilled in the art to which thedisclosure pertains. All references cited in this disclosure areincorporated by reference to the same extent as if each reference hadbeen incorporated by reference in its entirety individually.

It is to be understood that the disclosure is not limited to particularmethods or systems, which can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting. As used in this specification and the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontent clearly dictates otherwise. The term “plurality” includes two ormore referents unless the content clearly dictates otherwise. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which the disclosure pertains.

1.-14. (canceled)
 15. An implantable device comprising: a communicationsystem; a sensor; and a monolithic substrate comprising an integratedsensor circuit configured to process input from the sensor into a formconveyable by the communication system, and a power supply configured toreceive energy from an external source, wherein: the communicationsystem is located on a first face of the monolithic substrate and thesensor is located on a second face of the monolithic substrate, thefirst face being on an opposite side of the monolithic substrate fromthe second face, the sensor comprises a functionalized layer integratedinto the monolithic substrate, wherein the device is configured to bepowered for an interval of time corresponding to a period of time whenenergy is received by the power supply; and the communication systemcomprises an RF antenna.
 16. The implantable device of claim 15, whereinthe monolithic substrate has a height less than 200 microns
 17. Theimplantable device of claim 15, wherein the communication system furthercomprises a modulator and an output driver.
 18. The implantable deviceof claim 17, wherein the modulator comprises a control circuit and apulse width modulator.
 19. The implantable device of claim 15, whereinthe power supply comprises a second RF antenna.
 20. The implantabledevice of claim 15, wherein the monolithic substrate is a CMOS die. 21.The implantable device of claim 15, further comprising at least oneinterconnect electrically connecting the sensor to the communicationsystem, the interconnect going through the monolithic substrate.
 22. Theimplantable device of claim 21, wherein the at least one interconnect iscylindrical.
 23. The implantable device of claim 15, wherein the sensoris a glucose sensor.
 24. A system comprising the implantable deviceaccording to claim 1 and an external device, the external devicecomprising: a power source; a power transmitter; a processor connectedto the power transmitter and the power source, the processor configuredto pulse power to the implantable device by activating the powertransmitter only for an interval of time; and a detector that receivesinformation from the communication system of the implantable device. 25.The system according to claim 24 further comprising a communication linkto transmit information from the implantable device and operably linkedto the detector either directly or through the processor.
 26. The systemaccording to claim 24 further comprising a display operably connected tothe processor.
 27. The system according to claim 24 wherein the detectorcomprises a detector array.
 28. The system according to claim 24 whereinthe external device is a consumer electronics device.
 29. An implantabledevice comprising: a communication system; a sensor; and a monolithicsubstrate comprising an integrated sensor circuit configured to processinput from the sensor into a form conveyable by the communicationsystem, and a power supply configured to receive energy from an externalsource, wherein: the power supply comprises an RF antenna; thecommunication system is located on a first face of the monolithicsubstrate and the sensor is located on a second face of the monolithicsubstrate, the first face being on an opposite side of the monolithicsubstrate from the second face, the sensor comprises a functional layerintegrated into the monolithic substrate, wherein the functional layercomprises an enzyme, wherein the device is configured to be powered foran interval of time corresponding to a period of time when energy isreceived by the power supply, and the communication system.
 30. Theimplantable device of claim 29, wherein the communication systemcomprises a modulator and an output driver.
 31. The implantable deviceof claim 29, further comprising at least one interconnect electricallyconnecting the sensor to the communication system, the at least oneinterconnect going through the monolithic substrate.
 32. The implantabledevice of claim 29, wherein the sensor is a glucose sensor.
 33. Theimplantable device of claim 15, wherein the monolithic substrate has aheight less than 200 microns.